Novel Targeted Therapies for Pulmonary Fibrosis (P01). Idiopathic pulmonary fibrosis (IPF) is a major, progressive, fatal lung disorder of unknown etiology. It lacks any effective treatment. Promising therapies likely fail because poor lung delivery and tissue penetration have prevented sufficient local drug concentration to achieve efficacy without systemic toxicity. The ability to specifically deliver therapies into the lung tisue has tremendous advantages for patient care. This program project grant is designed to integrate synergistically the activities of 3 projects and 3 core facilities focused on creating and testing novel therapies for IPF. We will use a novel lung delivery platform to reduce toxicity and enhance targeted penetration and therapeutic efficacy of well-known anti-fibrotic biologic agents and small chemotherapeutic inhibitors of key pro-fibrotic signaling pathways mediating IPF. Our extensive vascular proteomic mapping has identified accessible targets on the lung endothelial cell surface that enable rapid and specific lung targeting. More importantly, we also discovered that targeting proteins concentrated in vesicular transporters at the EC surface called caveolae enable antibodies to overcome the normally restrictive EC barrier by pumping them across the vascular wall to reach inside lung tissue within minutes of intravenous injection. From these fundamental discoveries, we are proposing to translate our novel caveolae-targeting strategy into new, enhanced treatments for IPF. Project 1 will test how well this strategy can rapidly deliver and concentrate intravenously injected antibodies and their attached therapeutic cargo (anti-fibrotic protein or chemo-loaded nanogels) specifically in rodent and human lungs. Those antibodies and therapeutic agents that Project 1 determines are pumped effectively will now be used in Projects 2 and 3 to evaluate their targeting and efficacy in fibrotic lungs. Both projects will evaluate human clinical specimens from IPF patients to assess target expression, caveolae function and lung targeting in fibrosis. Core B will generate and characterize all of the retargete therapeutics for each project. Core C will provide to all projects multiple imaging capabilities to comprehensively track the lung targeting and tissue processing of each retargeted therapeutic agent after intravenous injection. The Administrative and Biostatistical Core A will make both administrative and statistical capabilities available to all projects to potentiate data management and the pace and quality of the P01 research. This P01 program may initiate a paradigm shift in how pulmonary therapies are delivered, offering hope for patients with IPF and other devastating lung diseases.